Voltage-gated ion channels

Voltage-gated ion channels (VGICs) are responsive to changes in the local electrical membrane potential, and are critical for the function of excitable cells, such as neurons and muscle cells. VGICs are ion-selective, with separate channels identified for each of the major physiological ions- Na⁺, K⁺, Ca²⁺, Cl^-. Each type of channel is a multimeric complex of subunits encoded by a number of genes. Subunit combinations vary in different tissues, with each combination having distinctive voltage dependence and cellular localization. Some VGICs are highly localized, such as the CatSper Ca channels, whose expression is restricted only to the principal piece of the sperm tail.

There are many drugs whose mechanism of action involves perturbation of VGIC activity. Some of the main classes of drugs are discussed below:

Calcium channel blockers (CCBs) -see also the topic 'Calcium channel blocking drugs' in the Cardiovascular system section of the Drugs module

Calcium-channel blockers are smooth-muscle relaxors having a negative inotropic effect on the working myocardial cells of the atria and ventricles, with inhibition of Ca²⁺ entry blunting the ability of Ca²⁺ to serve as an intracellular messenger.

The dihydropyridine class of CCB drugs block activity of L-type calcium channels. Examples of this drug class are amlodipine, felodipine, isradipine, lacidipine, nicardipine, and nimodipine which are used in the treatment of hypertension. In comparison to phenylalkylamine class CCBs such as verapamil, the dihydropyridines are relatively vascular selective in their mechanism of action in lowering blood pressure.

Sodium channel blockers

Class III antiarrhythmics are primarily sodium channel blocking agents, and include the prescription medicines dronedarone and amiodarone hydrochloride.

Many local anaesthetic agents are also sodium channel blockers, and include lidocaine, bupivacaine, prilocaine, mepivacaine, tetracaine and ropivacaine. Mechanistically these drugs bind to an intracellular portion of voltage-gated sodium channels blocking sodium influx into nerve cells, which prevents depolarization. Without depolarization, no initiation or conduction of a pain signal can occur.

Some anticonvulsants (antiepileptic drugs or AEDs) work at least in part, by blocking sodium channels. By inhibiting sodium (and/or calcium) channel activity, AEDs act to reduce the release of excitatory glutamate which is elevated in epilepsy and may also reduce γ-aminobutyric acid (GABA) secretion.

Whilst not strictly ion channel inhibitors, proton-pump inhibitors also block ion transport across the membrane. In this case by irreversibly blocking the H⁺/K⁺ ATPase transporter activity of the proton pump on the surface of gastric parietal cells. This action produces a pronounced and long-lasting reduction of gastric acid production. PPIs are the most potent inhibitors of acid secretion available, and have largely superseded histamine H₂ receptor antagonists which have similar effects, but a different mode of action. Prescription PPIs include omeprazole, esomeprazole, pantoprazole, lansoprazole, and rabeprazole.

The Transient Receptor Potential (TRP) superfamily of channels are found in sensory receptor cells that are involved in heat sensation, taste, smell, touch, and osmotic and volume regulation.